Project Summary/Abstract Chemicogenetic rescue of autism-like social deficits in Shank3-deficient mice A hallmark for autism spectrum disorders (ASD) is social deficits and restricted & repetitive behaviors. Presently, there is no known cure for ASD. The goal of this R03 proposal is to find a novel, mechanism-based intervention for potential treatment of ASD in a mouse model. ASD are often associated with abnormalities of the N-methyl- D-aspartate (NMDA) receptors function. Haploinsufficiency of the Shank3 gene due to deletion or de novo mutation has been linked to autism in human genetics studies. Our recent studies showed Shank3-deficient mice exhibit autism-like social deficits and restricted & repetitive behaviors, as well as the significantly diminished NMDA receptors synaptic function in prefrontal cortex (PFC), a brain region controlling high-level ?executive? functions, all of which are impaired in ASD. We hypothesize that using the chemicogenetic technology to elevate PFC pyramidal neuronal activity will rescue autism-like social and diminished NMDA receptors synaptic deficits in Shank3-deficient mice. To test this, combined electrophysiological, behavioral, molecular and biochemical approaches will be used to address two important questions: (1) Does chemicogenetic elevating the synaptic activity of PFC pyramidal neurons rescue autism-like behavioral and synaptic deficits in Shank3-deficient mice? (2) What are the molecular mechanisms underlying the rescuing effect of chemicogenetic activation of PFC pyramidal neurons on autistic deficits in Shank3-deficient mice? Results gained from this study will help to identify molecular and cellular targets for the design of novel therapeutic strategies for ASD.